2010 Grants - Falzone

New Models to Study the Role of Ubiquitin-Proteasome Axonal Transport in Alzheimer's Disease

2010 New Investigator Research Grant

Two key suspects in Alzheimer's disease are the protein fragment beta-amyloid and the protein tau. Alzheimer brains tend to feature clumplike plaques of beta-amyloid and tangle-like aggregates of abnormal tau. Recent studies have found that these accumulations may be associated with another protein called ubiquitin. In healthy brains, ubiquitin binds to harmful beta-amyloid and tau and targets them for destruction. But in people with Alzheimer's, ubiquitin activity appears to be diminished.

In preliminary research with cultured brain cells, Tomas Luis Falzone, Ph.D., and colleagues found that the progression of Alzheimer pathology was linked to dysfunction in the cells' axons. Axons are armlike cellular structures that help transport nutrients and other compounds around brain cells. In Alzheimer's disease, neuronal axons become damaged and lose their ability to transport vital compounds. The researchers hypothesize that this damage hinders the transportation of ubiquitin to sites where beta-amyloid and tau accumulate.

For their proposed grant, Dr. Falzone and colleagues plan to test this hypothesis. They will use cultured mouse cells to study in detail how ubiquitin may be transported along neuronal axons to different cellular sites. They will then induce ubiquitin transportation deficits in various cultured cells and determine how these deficits my lead to the production of harmful tau and beta-amyloid. The researchers will also use immature human stem cells to create a model human nerve cell with Alzheimer-related ubiquitin transportation deficits. These deficits, and their relationship to beta-amyloid and tau production, will be studied in detail.

The work of Dr. Falzone's team will clarify the complex role of ubiquitin in Alzheimer's disease. By working with stem cells, the researchers hope to create a cellular model that can be used as a basis for future human Alzheimer therapies.